Solubility is one of the key determinants of the bioavailability of a pharmaceutical agent. The dissolution of pharmaceutical agents in a pharmaceutically acceptable medium is the most preferred manner of formulation to deliver therapeutic agents, and many drug candidates do not reach the market due to their poor solubility.
Many attempts have been made to improve the solubility of insoluble compounds. These approaches include: reduction of particle size of a compound using techniques such as micronization and nanosuspensions; modification of the crystal habit of a compound; complexation with other agents such as cyclodextrins; dispersion of a compound in a highly soluble carrier; and solubilization of a compound using surfactants. Pinnamaneni et al., Pharmazie, 57(5): 291-300 (2002).
Among others, carrier agents are commonly used to dissolve the compounds that are otherwise insoluble. Most of the commonly used carrier agents, in particular, polyoxyethylene sorbitan monooleate (Polysorbate 80) and CREMOPHOR® EL, exhibit various clinical side effects, especially in children and newborns. For example, the currently approved formulation of paclitaxel, a commonly prescribed anti-cancer agent, contains 51% CREMOPHOR® EL and 49% ethanol. CREMOPHOR® EL is believed to cause hypersensitive reactions to paclitaxel treatments. In addition, CREMOPHOR® EL has been reported to decrease the bioavailability of paclitaxel. Baedelmeijer et al., Cancer Chemother. Pharmacol., 49: 119-125 (2002). This decrease in bioavailability necessitates the administration of higher doses of the paclitaxel formulation, which, in turn, results in a higher risk of hypersensitive reactions to the paclitaxel formulation. Moreover, in drug formulations, such as paclitaxel, in which ethanol is present in the formulation and high doses are required, acute ethanol toxicity is a concern.
Although there have been previous attempts to eliminate both CREMOPHOR® EL and ethanol in formulations of drug molecules (see, e.g., U.S. Pat. No. 5,415,869 (liposomal formulation), U.S. Pat. No. 5,580,075 (gas-filled liposomal formulation), U.S. Pat. No. 5,684,169 (complexation with cyclodextrin), U.S. Pat. No. 6,538,020 (fatty acid esterified with PEG), WO 99/13914 (HSA formulation) and U.S. Pat. No. 6,096,331 (protein shell containing oil)), a need still exists for a method to effectively solubilize a compound without the use of harmful agents, or modifying the compound itself.
In addition, there also exists a need for improved solubility of compounds outside the pharmaceutical context.